The treatment of pain, particularly neuropathic pain, is of great significance in the medical field. There is a global need for effective pain therapies. The urgent need for action to provide a patient-friendly and specific treatment for chronic and non-chronic states of pain, this being taken to mean the successful and satisfactory treatment of pain for patients, is documented by the large number of scientific papers which have recently appeared in the field of applied analgetics or in basic research concerning nociception.
A suitable starting point for the treatment of pain; particularly pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain and more preferably neurophatic pain; is the vanilloid receptor of subtype 1 (VR1/TRPV1), which is frequently also referred to as the capsaicin receptor. This receptor is stimulated, inter alia, by vanilloids such as capsaicin, heat, and protons and plays a central part in the generation of pain. Furthermore, it is significant for a large number of other physiological and pathophysiological processes such as migraine; depression; neurodegenerative disorders; cognitive disorders; anxiety; epilepsy; coughing; diarrhoea; pruritus; cardiovascular disorders; food intake disorders; medicine addiction; medicine abuse and, in particular, urinary incontinence.
It is thus an object of the invention to provide novel compounds which are particularly suitable for use as pharmacological active substances in medicinal drugs, preferably in medicinal drugs for treatment of disorders or diseases that are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1 receptors).
It has now been found, surprisingly, that substituted cyclic urea derivatives of the following general formula I have excellent affinity toward the vanilloid receptor of subtype 1 (VR1/TRPV1 receptor) and are therefore particularly suitable for the prophylaxis and/or treatment of disorders or diseases that are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1).
The present invention therefore relates to substituted cyclic urea derivatives of the general formula I,
in which    X stands for O, S or N—C≡N;    m is equal to 1 or 2;    n is equal to 1 or 2;    p1 and p2 independently            stand for 0, 1, 2, or 3, the sum of p1 and p2 being 1, 2, or 3;            R1, R2, R3, R4, R5, R8, R9, R10, R11 and R12 independently            stand for H; F; Cl; Br; I; —SF5; —NO2; —NH2; —OH; —SH; —C(═O)—NH2;        —S(═O)2—NH2;        —NR13R14; —NH—R15; —OR16; —SR17; —O—(CH2)a—R18; —O—(CH2)b—OR19;        —(CH2)c—O—(CH2)d—OR20;        —(CH2)e—O—C(═O)—R21;        —(CH2)f—O—C(═O)—OR22;        —NR23S(═O)2R24;        —(CH2)g—C(═O)—NR25R26;        —(CH2)h—C(═O)—NH—R27;        —S(═O)iR28;        —(CH2)j—S(═O)2—NR29R30;        —(CH2)k—S(═O)2—NHR31;        —(CH2)l—NR32—C(═O)(CH2)q—OR33;        —(CH2)r—NH—C(═O)(CH2)s—OR34;        —(CH2)t—NR35—O—C(═O)—OR36;        —(CH2)u—NH—O—C(═O)—OR37;        —(CH2)v—O—S(═O)2—R38;        —(CH2)w—NR39—C(═O)—SR40;        —(CH2)y—C(═O)—NH—OR41;        —P(═O)(OR42)2;        —(CH2)z—C(═S)—NR43R44;        —(CH2)aa—C(═S)—NH—R45;        —(CH2)bb—NR46—C(═O)—R47;        —(CH2)cc—NH—C(═O)—R48;        or —NH—C(═NH)—NH2;        with a, b, c, d, q and s independently standing for 1, 2, 3, 4, or 5 and        e, f, g, h, j, k, l, r, t, u, v, w, x, y, z, aa, bb and cc independently standing for 0, 1, 2, 3, 4, or 5, and        i being equal to 1 or 2        for a linear or branched, saturated or unsaturated aliphatic C1-10 radical, which can optionally be substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O(C1-5 alkyl), —S(C1-5 alkyl), —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), —OCF3 and —SCF3;        or for an optionally substituted six-membered or ten-membered aryl radical, which can be bonded via a linear or branched, optionally substituted C1-5 alkylene group;        or two adjacent radicals selected from the group consisting of R8, R9, R10, R11 and R12 together stand for a methylenedioxy(—O—CH2—O) group;        provided that at least one of the radicals R8, R9, R10, R11 and R12 stands for —NR23S(═O)2R24;            R6 and R7 each stand for a hydrogen radical    or    R6 and R7, together with the interconnecting C—C bridge, form an unsubstituted phenylene radical;    R13, R14, R15, R16, R17, R19, R20, R21, R22, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47 and R48             independently        stand for a linear or branched, saturated or unsaturated aliphatic C1-10 radical, which can be optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O(C1-5 alkyl), —S(C1-5 alkyl), —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), —OCF3, and —SCF3;        or for an unsaturated or saturated, optionally substituted three-membered, four-membered, five-membered, six-membered, seven-membered, eight-membered, or nine-membered cycloaliphatic radical        or for an optionally substituted five-membered to fourteen-membered aryl radical or an optionally substituted five-membered to fourteen-membered heteroaryl radical, which can be condensed with a saturated or unsaturated, optionally substituted monocyclic or polycyclic ring system;            R18 stands for an unsaturated or saturated, optionally substituted three-membered, four-membered, five-membered, six-membered, seven-membered, eight-membered, or nine-membered cycloaliphatic radical            or for an optionally substituted five-membered to fourteen-membered aryl radical or an optionally substituted five-membered to fourteen-membered heteroaryl radical, which can be condensed with a saturated or unsaturated, optionally substituted monocyclic or polycyclic ring system;            R23 stands for a hydrogen radical            or for a linear or branched, saturated or unsaturated or aliphatic C1-10 radical, which can optionally be substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O(C1-5 alkyl), —S(C1-5 alkyl), —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), —OCF3, and —SCF3;            and    R24 stands for a linear or branched, saturated or unsaturated or aliphatic C1-10 radical, which can optionally be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of —CN, —NO2, —OH, —NH2, —SH, —O(C1-5 alkyl), —S(C1-5 alkyl), —NH(C1-5 alkyl), and —N(C1-5 alkyl)(C1-5 alkyl),            or for an optionally substituted 5-membered to 14-membered aryl or heteroaryl radical, which may be condensed with a saturated or unsaturated, optionally substituted mono-oder poly-cyclic ring system;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Preferably, the aforementioned cycloaliphatic radicals can optionally in each case be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5 alkyl, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—C1-5 alkyl, —C1-5 alkyl, —C(═O)—OH, —C(═O)—O—C1-5 alkyl, —NH—C1-5 alkyl, —N(C1-5 alkyl)2, —O-phenyl, —O-benzyl, phenyl, and benzyl, and in each case the cyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzyl can be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —C1-5 alkyl, —O—C1-5 alkyl, —O—CF3, —S—CF3, phenyl, and —O-benzyl, and in each case optionally exhibit 1, 2, 3, 4, or 5 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen, and sulfur as ring member(s).
Preferably, the aforementioned C1-5 alkylene group can optionally be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —SH, —NH2, —CN, and NO2.
In another preferred embodiment the rings of the aforementioned monocyclic or polycyclic ring systems can optionally in each case be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-15 alkyl, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—C1-5 alkyl, —C1-5 alkyl, —C(═O)—OH, —C(═O)—O—C1-5 alkyl, —NH—C1-5 alkyl, —N(C1-5 alkyl)2, —O-phenyl, —O-benzyl, phenyl, and benzyl, and in each case the cyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzyl can be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —C1-5 alkyl, —O—C1-5 alkyl, —O—CF3, —S—CF3, phenyl, and —O-benzyl.
Preferably, the rings of the aforementioned monocyclic or polycyclic ring systems are each five-membered, six-membered, or seven-membered and can in each case optionally exhibit 1, 2, 3, 4, or 5 heteroatom(s) as ring member(s), which are independently selected from the group consisting of oxygen, nitrogen, and sulfur.
In another preferred embodiment, the aforementioned aryl radicals or heteroaryl radicals can optionally in each case be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5 alkyl, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—C1-5 alkyl, —C1-5 alkyl, —C(═O)—OH, —C(═O)—O—C1-5 alkyl, —NH—C1-5 alkyl, —N(C1-5 alkyl)2, —NH—C(═O)—O—C1-5 alkyl, —C(═O)—H, —C(═O)—C1-5 alkyl, —C(═O)—NH2, —C(═O)—NH—C1-5 alkyl, —C(═O)—N—(C1-5 alkyl)2, —O-phenyl, —O-benzyl, phenyl, and benzyl, and in each case the cyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzyl can be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF2, —SF1-5, —CN, —NO1-5, —C3 alkyl, —O—C3 alkyl, —O—CF3, —S—CF3, phenyl, and —O-benzyl.
In another preferred embodiment, the aforementioned heteroaryl radicals in each case comprise 1, 2, 3, 4, or 5 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen, and sulfur as ring member(s).
If one or more of the substituents R1 to R5, R8 to R17, R19 to R23 and R25 to R48 stand for a saturated or unsaturated C1-10 aliphatic radical, ie for a C1-10 alkyl, C2-10 alkenyl, or C2-10 alkinyl radical, this can preferably be substituted by optionally 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —O(C1-5 alkyl), —S(C1-5 alkyl), —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), —OCF3, and —SCF3. C2-10 alkenyl radicals have at least one, preferably 1, 2, 3, or 4 C—C double bonds and C2-10 alkinyl radicals have at least one, preferably 1, 2, 3, or 4 C—C triple bonds.
Preference is given to alkyl radicals selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, and n-hexyl, which can optionally be substituted by 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH3, —SH, —OCH5, —O—C2H5, —SCH3, —S—C2H5, —OCF3, —SCF3, —NH—CH3, —N(CH3)2, —N(C2H5)2, and —N(CH3)(C2H5).
In another preferred embodiment, alkenyl radicals are selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbuten-2-yl, 1-pentenyl, 2-pentenyl, 3-pentenyl, and 4-pentenyl, which can optionally be substituted by 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —OCH5, —O—C2H5, —SCH3, —S—C2H5, —OCF3, —SCF3, —NH—CH3, —N(CH3)2, —N(C2H5)2, and —N(CH3)(C2H5).
Preference is also given to alkinyl radicals selected from the group consisting of ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl, and 3-butinyl, which can optionally be substituted by 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —NH2, —SH, —OCH3, —O—C2H5, —SCH3, —S—C2H5, —OCF3, —SCF3, —NH—CH3, —N(CH3)2, —N(C2H5)2, and —N(CH3)(C2H5).
Very preferred optionally substituted C1-10 aliphatic radicals are selected from the group consisting of methyl, —CF3, —CCl3, —CBr3, —CH2—CN, —CH2—O—CH3, —CH2—O—CF3, —CH2—SF3, —CH2—NH2, —CH2—OH, —CH2—SH, —CH2—NH—CH3, —CH2—N(CH3)2, —CH2—N(C2H5)2, —CH2—N(CH3)(C2H5), ethyl, —CH2—CH2—NH2, —CH2—CH2—OH, —CH2—CH2—SH, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)2, —CH2—CH2—N(C2H5)2, —CH2—CH2—N(CH3)(C2H5), —CH2—CF3, —C2F5, —CH2—CCl3, —CH2—CBr3, —CH2—CH2—CN, n-propyl, —CH2—CH2—CH2—OH, —CH2—CH2—CH2—SH, —CH2—CH2—CH2—NH2, —CH2—CH2—CH2—NH—CH3, —CH2—CH2—CH2—N(CH3)2, —CH2—CH2—CH2—N(C2H5)2, —CH2—CH2—CH2—N(CH3)(C2H5), —CH2—CH2—O—CH3, —CF2—CF2—CF3, —CF(CF3)2, isopropyl, —CH2—CH2—CH2—CN, —CH2—O—CH2—CH3, —CH2—CH2—SF3, —CH2—CH2—OCF3, —CH(CH3)(O—CH3), —CH(CH3)(S—CH3), n-butyl, —CF2—CF2—CF2—CF3, —CH2—CH2—CH2—CH2—CN, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbuten-2-yl, (1,1,2)-trifluoro-1-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, and 4-pentenyl.
If the substituent R24 stands for a saturated or unsaturated C1-10 aliphatic radical, ie for a C1-10 alkyl, C2-10 alkenyl, or C2-10 alkinyl radical, this can preferably be substituted by optionally 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of —CN, —NO2, —OH, —NH2, —SH, —O(C1-5 alkyl), —S(C1-5 alkyl), —NH(C1-5 alkyl), and —N(C1-5 alkyl)(C1-5 alkyl). C2-10 alkenyl radicals exhibit at least one, preferably 1, 2, 3, or 4 C—C double bonds and C2-10 alkinyl radicals at least one, preferably 1, 2, 3, or 4 C—C triple bonds.
Preferably, R24 stands for an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, and n-hexyl, which can optionally be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of —OH, —NH2, —SH, —NO2, —O—CH3, —S—CH3, —O—C2H5, —S—C2H5, —NH—CH3, —N(CH3)2, and —CN.
In another preferred embodiment, R24 stands for an alkenyl radical selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbuten-2-yl, 1-pentenyl, 2-pentenyl, 3-pentenyl, and 4-pentenyl, which can optionally be substituted by 1, 2, or 3 substituents independently selected from the group consisting of —OH, —NH2, —SH, —NO2, —O—CH3, —S—CH3, —O—C2H5, —S—C2H5, —NH—CH3, —N(CH3)2, and —CN.
In another preferred embodiment, R24 stands for an alkinyl radical selected from the group consisting of ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl, and 3-butinyl, which can optionally be substituted by 1, 2, or 3 substituents independently selected from the group consisting of —OH, —NH2, —SH, —NO2, —O—CH3, —S—CH3, —O—C2H5, —S—C2H5, —NH—CH3, —N(CH3)2, and —CN.
More preferably, R24 stands for an optionally substituted C1-10 aliphatic radical selected from the group consisting of methyl, —CH2—CN, —CH2—O—CH3, ethyl, —CH2—CH3—CN, n-propyl, —CH2—CH2—O—CH3, isopropyl, —CH2—CH2—CH2—CN, —CH2—O—CH2—CH3, —CH(CH3)(O—CH3), —CH(CH3)(S—CH3), n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbuten-2-yl, 1-pentenyl, 2-pentenyl, 3-pentenyl, and 4-pentenyl.
If one or more of the substituents R13 to R22 and R25 to R48 stand for a (hetero)cycloaliphatic radical, this can preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, azepanyl, diazepanyl, and dithiolanyl.
More preferably, the (hetero)cycloaliphatic radicals can optionally in each case be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C(CH3)3, —NH2, —NO2, —O—CF3, —SCF3, —SH, —S—CH3, —S—C2H5, —S—C(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, —C(═O)—OH, —C(═O)—O—CH3, —C(═O)—O—C2H5, —N(CH3)2, —N(C2H5)2, —N(H)(CH3), —N(H)(C2H5), —O-phenyl, —O-benzyl, phenyl, and benzyl, and in each case the cyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzyl can be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —O—CH3, —O—C2H5, —O—C(CH3)3, —O—CF3, —S—CF3, phenyl, and —O-benzyl.
If one or more of the substituents R1 to R5, R8 to R22, and R24 to R48 stand for an aryl radical, this can preferably be selected from the group consisting of phenyl and naphthyl (1-naphthyl and 2-naphthyl).
If one or more of the substituents R13 to R22 and R24 to R48 stand for a heteroaryl radical, this can preferably be selected from the group consisting of thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl.
More preferably, the aryl radicals or heteroaryl radicals can optionally in each case be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C(CH3)3, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—CH3, —S—C2H5, —S—C(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, —C(═O)—OH, —C(═O)—O—CH3, —C(═O)—O—C2H5, —N(CH3)2, —N(C2H5)2, —N(H)(CH3), —N(H)(C2H5), —NH—C(═O)—O—CH3, —NH—C(═O)—O—C2H5, —NH—C(═O)—O—C(CH3)2, —C(═O)—H, —C(═O)—CH3, —C(═O)—C2H5, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)-nH—C2H5, —C(═O)—N—(CH3)2, —C(═O)—N—(C2H5)2, —O-phenyl, —O-benzyl, phenyl, and benzyl, and in each case the cyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzyl can be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —O—CH3, —O—C2H5, —O—C(CH3)3, —O—CF3, —S—CF3, phenyl, and —O-benzyl.
For the purposes of the present invention, a monocyclic or polycyclic ring system is to be understood as meaning monocyclic or polycyclic hydrocarbon groups, which can be saturated or unsaturated and optionally comprise 1, 2, 3, 4, or 5 heteroatom(s) as ring member(s), which are independently selected from the group consisting of oxygen, nitrogen, and sulfur. Such a monocyclic or polycyclic ring system can, for example, be condensed (anellated) with an aryl radical or a heteroaryl radical.
If a polycyclic ring system such as a bicyclic ring system is present, the various rings can independently exhibit a different degree of saturation, ie be saturated or unsaturated. A polycyclic ring system is preferably a bicyclic ring system.
As examples of aryl radicals condensed with a monocyclic or polycyclic ring system mention may be made of (1,3)-benzodioxolyl and (1,4)-benzodioxanyl.
If one or more of the substituents R13 to R22 and R24 to R48 have a monocyclic or polycyclic ring system, this can preferably be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—CH3, —O—C2H5, —O—C(CH3)3, —NH2, —NO2, —O—CF3, —SCF3, —SH, —S—CH3, —S—C2H5, —S—C(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, —C(═O)—OH, —C(═O)—O—CH3, —C(═O)—O—C2H5, —N(CH3)2, —N(C2H5)2, —N(H)(CH3), —N(H)(C2H5), —O-phenyl, —O-benzyl, phenyl, and benzyl, and in each case the cyclic moiety of the radicals —O-phenyl, —O-benzyl, phenyl, and benzyl can be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —O—CH3, —O—C2H5, —O—C(CH3)3, —O—CF3, —S—CF3, phenyl, and —O-benzyl.
If one or more of the substituents R1 to R5 and R8 to R12 comprise a linear or branched C1-5 alkylene group, this can preferably be selected from the group consisting of —(CH2)—, —(CH2)2—, —C(H)(CH3)—, —(CH2)3—, —(CH2)4—, —(CH2)5—, —C(H)(C(H)(CH3)2)—, and —C(C2H5)(H)—.
Preference is given to substituted cyclic urea derivatives of the above general formula I, in which    R1, R2, R4, and R5 each independently            stand for H; F; Cl; Br; I; —SF5; —NO2; —NH2; —OH; —SH; —C(═O)—NH2;        —S(═O)2—NH2;        —NR13R14; —NH—R15; —OR16; —SR17; —O—(CH2)a—R18; —O—(CH2)b—OR19;        —(CH2)c—O—(CH2)d—OR20;        —(CH2)e—O—C(═O)—R21;        —(CH2)fO—C(═O)—OR22;        —NR23S(═O)2R24;        —(CH2)g—C(═O)—NR25R26;        (CH2)h—C(═O)—NH—R27;        —S(═O)iR28;        —(CH2)j—S(═O)2—NR29R30;        —(CH2)k—S(═O)2—NHR31;        —(CH2)l—NR32—C(═O)(CH2)q—OR33;        —(CH2)r—NH—C(═O)(CH2)s—OR34;        —(CH2)t—NR35—O—C(═O)—OR36;        —(CH2)u—NH—O—C(═O)—OR37;        —(CH2)v—O—S(═O)2—R38;        —(CH2)w—NR39—C(═O)—SR40;        —(CH2)y—C(═O)—NH—OR41;        —P(═O)(OR42)2;        —(CH2)z—C(═S)—NR43R44;        —(CH2)aa—C(═S)—NH—R45;        —(CH2)bb—NR46—C(═O)—R47;        —(CH2)cc—NH—C(═O)—R48;        or —NH—C(═NH)—NH2;        with a, b, and c, d, q and s each being independently equal to 1, 2, 3, 4, or 5,        e, f, and g, h, j, k, l, r, t, u, v, w, x, y, and z, aa, bb and cc each being independently equal to 1, 1, 2, 3, 4, or 5 and        i being equal to 1 or 2;        or for a radical selected from the group consisting of methyl, —CF3, —CCl3, —CBr3, —CH2—CN, —CH2—O—CH3, —CH2—O—CF3, —CH2—SF3, —CH2—NH2, —CH2—OH, —CH2—SH, —CH2—NH—CH3, —CH2—N(CH3)2, —CH2—N(C2H5)2, —CH2—N(CH3)(C2H5), ethyl, —CH2—CH2—NH2, —CH2—CH2—OH, —CH2—CH2—SH, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)2, —CH2—CH2—N(C2H5)2, —CH2—CH2—N(CH3)(C2H5), —CH2—CF3, —C2F5, —CH2—CCl3, —CH2—CBr3, —CH2—CH2—CN, n-propyl, —CH2—CH2—CH2—OH, —CH2—CH2—CH2—SH, —CH2—CH2—CH2—NH2, —CH2—CH2—CH2—NH—CH3, —CH2—CH2—CH2—N(CH3)2, CH2—CH2—CH2—N(C2H5)2, —CH2—CH2—CH2—N(CH3)(C2H5), —CH2—CH2—O—CH3, —CF2—CF2—CF3, —CF(CF3)2, isopropyl, —CH2—CH2—CH2—CN, —CH2—O—CH2—CH3, —CH2—CH2—SF3, —CH2—CH2—OCF3, —CH(CH3)(O—CH3), —CH(CH3)(S—CH3), n-butyl, —CF2—CF2—CF2—CF3, —CH2—CH2—CH2—CH2—CN, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbuten-2-yl, (1,1,2)-trifluoro-1-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, and 4-pentenyl;        or for an aryl radical selected from the group consisting of phenyl and naphthyl, wherein the aryl radical can be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —SH, methyl, ethyl, —CF3, —O—CF3, —S—CF3, —SF5, —O—CH3, —O—C2H5, —NH2, —N(CH3)2, —N(C2H5)2, —N(H)(CH3), and —N(H)(C2H5);            and    R3 stands for F; Cl; Br; I; —SF5; —NO2; —NH2; —OH; —SH; —C(═O)—NH2; —S(═O)2—NH2; —NR13R14; —NH—R15; —OR16; —SR17; —O—(CH2)a—R18, —O—(CH2)b—OR19, or —NR23S(═O)2R24;            wherein        a and b are each independently equal to 1, 2, 3, 4, or 5;        or for a radical selected from the group consisting of methyl, —CF3, —CCl3, —CBr3, —CH2—CN, —CH2—O—CH3, —CH2—O—CF3, —CH2—SF3, —CH2—NH2, —CH2—OH, —CH2—SH, —CH2—NH—CH3, —CH2—N(CH3)2, —CH2—N(C2H5)2, —CH2—N(CH3)(C2H5), ethyl, —CH2—CH2—NH2, —CH2—CH2—OH, —CH2—CH2—SH, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)2, —CH2—CH2—N(C2H5)2, —CH2—CH2—N(CH3)(C2H5), —CH2—CF3, —C2F5, —CH2—CCl3, —CH2—CBr3, —CH2—CH2—CN, n-propyl, —CH2—CH2—CH2—OH, —CH2—CH2—CH2—SH, —CH2—CH2—CH2—NH2, —CH2—CH2—CH2—NH—CH3, —CH2—CH2—CH2—N(CH3)2, —CH2—CH2—CH2—N(C2H5)2, —CH2—CH2—CH2—N(CH3)(C2H5), —CH2—CH2—O—CH3, —CF2—CF2—CF3, —CF(CF3)2, isopropyl, —CH2—CH2—CH2—CN, —CH2—O—CH2—CH3, —CH2—CH2—SF3, —CH2—CH2—OCF3, —CH(CH3)(O—CH3), —CH(CH3)(S—CH3), n-butyl, —CF2—CF2—CF2—CF3, —CH2—CH2—CH2—CH2—CN, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbuten-2-yl, (1,1,2)-trifluoro-1-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, and 4-pentenyl;and X, m, n, p1, p2, and R6 to R48 each have the meanings stated above, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Preference is also given to substituted cyclic urea derivatives of the above general formula I, in which    R1, R2, R4, and R5 each independently            stand for H; F; Cl; I; Br; —NO2; —NH2; —OH; and —SH; —NR13R14; —NH—R15; —OR16; —SR17; —NR23S(═O)2R24;        or for a radical selected from the group consisting of methyl, —CF3, ethyl, —CH2—CF3, —C2F5, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, or n-pentyl            and    R3 stands for F; Cl; Br; I; —OR2; —NR23S(═O)2R24;            or for a radical selected from the group consisting of —SF5, —CF3, —C2F5, —CH2—CF3, —CF(CF3)2, isopropyl, —CH(CH3)(O—CH3), —CH(CH3)(S—CH3), sec-butyl, isobutyl, and tert-butyl;and X, m, n, p1, p2, and R6 to R48 each have the meanings stated above, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Preference is also given to substituted cyclic urea derivatives of the above general formula I, in which    R8, R9, R11, and R12 each independently            stand for H; F; Cl; Br; I; —SF5; —NO2; —NH2; —OH; —SH;        —C(═O)—NH2; —S(═O)2—NH2;        —NR13R14; —NH—R15; —OR16; —SR17; —O—(CH2)a—R18; —O—(CH2)b—OR19;        —(CH2)c—O—(CH2)d—OR20;        —(CH2)e—O—C(═O)—R21;        —(CH2)f—O—C(═O)—OR22;        —NR23S(═O)2R24;        —(CH2)g—C(═O)—NR25R26;        —(CH2)h—C(═O)—NH—R27;        —S(═O)iR28;        —(CH2)j—S(═O)2—NR29R30;        —(CH2)k—S(═O)2—NHR31;        —(CH2)l—NR32—C(═O)(CH2)q—OR33;        —(CH2)r—NH—C(═O)(CH2)s—OR34;        —(CH2)t—NR35—O—C(═O)—OR36;        —(CH2)u—NH—O—C(═O)—OR37;        —(CH2)v—O—S(═O)2—R38;        —(CH2)w—NR39—C(═O)—SR40;        —(CH2)y—C(═O)—NH—OR41;        —P(═O)(OR42)2;        —(CH2)z—C(═S)—NR43R44;        (CH2)aa—C(═S)—NH—R45;        —(CH2)bb—NR46—C(═O)—R47;        —(CH2)cc—NH—C(═O)—R48;        oder —NH—C(═NH)—NH2;        with a, b, and c, d, q, and s each being independently equal to 1, 2, 3, 4, or 5,        e, f, and g, h, j, k, l, r, t, u, v, w, x, y, and z, aa, bb and cc, each being independently equal to 0, 1, 2, 3, 4, or 5, and        i being equal to 1 or 2;        or for a radical selected from the group consisting of methyl, —CF3, —CCl3, —CBr3, —CH2—CN, —CH2—O—CH3, —CH2—O—CF3, —CH2—SF3, —CH2—NH2, —CH2—OH, —CH2—SH, —CH2—NH—CH3, —CH2—N(CH3)2, —CH2—N(C2H5)2, —CH2—N(CH3)(C2H5), ethyl, —CH2—CH2—NH2, —CH2—CH2—OH, —CH2—CH2—SH, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)2, —CH2—CH2—N(C2H5)2, —CH2—CH2—N(CH3)(C2H5), —CH2—CF3, —C2F5, —CH2—CCl3, —CH2—CBr3, —CH2—CH2—CN, n-propyl, —CH2—CH2—CH2—OH, —CH2—CH2—CH2—SH, —CH2—CH2—CH2—NH2, —CH2—CH2—CH2—NH—CH3, —CH2—CH2—CH2—N(CH3)2, —CH2—CH2—CH2—N(C2H5)2, —CH2—CH2—CH2—N(CH3)(C2H5), —CH2—CH2—O—CH3, —CF2—CF2—CF3, —CF(CF3)2, isopropyl, —CH2—CH2—CH2—CN, —CH2—O—CH2—CH3, —CH2—CH2—SF3, —CH2—CH2—OCF3, —CH(CH3)(O—CH3), —CH(CH3)(S—CH3), n-butyl, —CF2—CF2—CF2—CF3, —CH2—CH2—CH2—CH2—CN, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbuten-2-yl, (1,1,2)-trifluoro-1-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, and 4-pentenyl;        or for an aryl radical selected from the group consisting of phenyl and naphthyl, wherein the aryl radical can be substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —SH, methyl, ethyl, —CF3, —O—CF3, —S—CF3, —SF5, —O—CH3, —O—C2H5, —NH2, —N(CH3)2, —N(C2H5)2, —N(H)(CH3), and —N(H)(C2H5);            and    R10 stands for —NR23S(═O)2R24;and X, m, n, p1, and p2, R1 to R7 and R13 to R48 each have the aforementioned meanings, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Preference is also given to substituted cyclic urea derivatives of the above general formula I, in which    R8, R9, R11, and R12 each independently            stand for H; F; Cl; Br; I; —NO2; —NH2; —OH; —SH; —NR13R14; —NH—R15; —OR16; —SR17; or —NR23S(═O)2R24;        or for a radical selected from the group consisting of methyl, —CF3, ethyl, —CH2—CF3, —C2F5, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, or n-pentyl            and    R10 stands for —NR23S(═O)2R24;and X, m, n, p1, and p2, R1 to R7 and R13 to R48 each have the meanings stated above, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Preference is also given to substituted cyclic urea derivatives of the above general formula I, in which    the radical R10 stands for —NR23S(═O)2R24 and the radicals R8, R9, R11, and R12 in each case stand for H;and X, m, n, p1, and p2, R1 to R7 and R13 to R48 each have the meanings stated above, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Preference is also given to substituted cyclic urea derivatives of the above general formula I, in which    the radical R3 stands for —OR16; —NR23S(═O)2R24; or for a radical selected from the group consisting of isopropyl, sec-butyl, isobutyl, and tert-butyl; and the radicals R1, R2, R4, and R5 in each case stand for H;and X, m, n, p1, p2, R5 bis R48 each have the meanings stated above, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Preference is also given to substituted cyclic urea derivatives of the above general formula I, in which    R13, R14, R15, R16, R17, R19, R20, R21, R22, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, and R48             independently stand for a radical selected from the group consisting of methyl, —CF3, —CCl3, —CBr3, —CH2—CN, —CH2—O—CH3, —CH2—O—CF3, —CH2—SF3, —CH2—NH2, —CH2—OH, —CH2—SH, —CH2—NH—CH3, —CH2—N(CH3)2, —CH2—N(C2H5)2, —CH2—N(CH3)(C2H5), ethyl, —CH2—CH2—NH2, —CH2—CH2—OH, —CH2—CH2—SH, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)2, —CH2—CH2—N(C2H5)2, —CH2—CH2—N(CH3)(C2H5), —CH2—CF3, —C2F5, —CH2—CCl3, —CH2—CBr3, —CH2—CH2—CN, n-propyl, —CH2—CH2—CH2—OH, —CH2—CH2—CH2—SH, —CH2—CH2—CH2—NH2, —CH2—CH2—CH2—NH—CH3, —CH2—CH2—CH2—N(CH3)2, —CH2—CH2—CH2—N(C2H5)2, —CH2—CH2—CH2—N(CH3)(C2H5), —CH2—CH2—O—CH3, —CF2—CF2—CF3, —CF(CF3)2, isopropyl, —CH2—CH2—CH2—CN, —CH2—O—CH2—CH3, —CH2—CH2—SF3, —CH2—CH2—OCF3, —CH(CH3)(O—CH3), —CH(CH3)(S—CH3), n-butyl, —CF2—CF2—CF2—CF3, —CH2—CH2—CH2—CH2—CN, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbuten-2-yl, (1,1,2)-trifluoro-1-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, and 4-pentenyl;        or for a (hetero)cycloaliphatic radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, azepanyl, diazepanyl, and dithiolanyl, wherein the (hetero)cycloaliphatic radical can in each case be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —NH2, —O—CF3, —SH, —O—CH3, —O—C2H5, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, —S—CH3, —S—C2H5, —C(═O)—O—CH3, —C(═O)—O—C2H5, Oxo (═O), —N(CH3)2, —N(C2H5)2, —N(H)(CH3), —N(H)(C2H5), —NO2, —SCF3, —C(═O)—OH, —O-phenyl, —O-benzyl, phenyl, and benzyl,        or for a radical selected from the group consisting of phenyl, naphthyl, (1,3)-benzodioxolyl, (1,4)-benzodioxanyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl, wherein the radical can in each case be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, —CF3, —O—CF3, —S—CF3, —SF5, —O—CH3, —O—C2H5, —O-phenyl, —O-benzyl, —NH2, —N(CH3)2, —N(C2H5)2, —N(H)(CH3) and —N(H)(C2H5);and X, m, n, p1, p2, R1 bis R12, R18, R23 and R24 each have the meanings stated above, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Preference is also given to substituted cyclic urea derivatives of the above general formula I, in which    R18 stands for a (hetero)cycloaliphatic radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, azepanyl, diazepanyl, and dithiolanyl, wherein the (hetero)cycloaliphatic radical can in each case be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —NH2, —O—CF3, —SH, —O—CH2, —O—C2H5, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, —S—CH3, —S—C2H5, —C(═O)—O—CH3, —C(═O)—O—C2H5, Oxo (═O), —N(CH3)2, —N(C2H5)2, —N(H)(CH3), —N(H)(C2H5), —NO2, —SCF3, —C(═O)—OH, —O-phenyl, —O-benzyl, phenyl, and benzyl,            or for a radical selected from the group consisting of phenyl, naphthyl, (1,3)-benzodioxolyl, (1,4)-benzodioxanyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl, wherein the radical can in each case be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, —CF3, —O—CF3, —S—CF3, —SF5, —O—CH3, —O—C2H5, —O-phenyl, —O-benzyl, —NH2, —N(CH3)2, —N(C2H5)2, —N(H)(CH3) and —N(H)(C2H5);and X, m, n, p1, and p2, R1 bis R17 and R19 bis R48 each have the meanings stated above, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Preference is also given to substituted cyclic urea derivatives of the above general formula I, in which    R23 stands for a hydrogen radical            or for a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, and n-hexyl;and X, m, n, p1, and p2, R1 to R22 and R24 to R48 each have the meanings stated above, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
Preference is also given to substituted cyclic urea derivatives of the above general formula I, in which    R24 stands for a radical selected from the group consisting of methyl, —CH2—CN, ethyl, —CH2—CH2—CN, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, and n-hexyl;and X, m, n, p1, and p2, R1 to R23 and R25 to R48 each have the meanings stated above, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Preference is also given to substituted cyclic urea derivatives of the above general formula I, in which    p1 and p2 each independently            stand for 0 or 1, the sum of p1 and p2 being 0 or 1;and X, m, n, and R1 bis R48 each have the meanings stated above, in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.        
It will be clear to the person skilled in the art that the situation in which p1 and p2 are each equal to 0 will result in a compound of the general formula Ic:

It will likewise be clear to the person skilled in the art that the situation in which p1 is equal to 0 and p2 is equal to 1 will result in the general formula Id:

It will also be clear to the person skilled in the art that the situation in which p1 is equal to 1 and p2 is equal to 0 will result in a compound of the general formula Ie:

It will likewise be clear to the person skilled in the art that the situation in which R6 and R7 together with the interconnecting C—C bridge form an unsubstituted phenylene radical will result in a compound of the general formula If:

Special preference is given to substituted cyclic urea derivatives of the above general formula I in which    X stands for O, S or N—C≡N;    m is equal to 1;    n is equal to 1;    p1 and p2 each independently            stand for 0 or 1, the sum of p1 and p2 being 0 or 1;            R1, R2, R4, R5, R8, R9, R11, and R12 each independently            stand for H; F; Cl; I; Br; —NO2; —NH2; —OH; —SH; —NR13R14; —NH—R15; —OR16; —SR17; or —NR23S(═O)2R24;        or for a radical selected from the group consisting of methyl, —CF3, ethyl, —CH2—CF3, —C2F5, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, or n-pentyl;            R3 stands for F; Cl; Br; I; —O—R16; —NR23S(═O)2R24;            or for a radical selected from the group consisting of —SF5, —CF3, —C2F5, —CH2—CF3, —CF(CF3)2, isopropyl, —CH(CH3)(O—CH3), —CH(CH3)(S—CH3), sec-butyl, isobutyl, and tert-butyl;            R6 and R7 each stand for a hydrogen radical    or    R6 and R7, together with the interconnecting C—C bridge, form an unsubstituted phenylene radical;    R10 stands for —NR23S(═O)2R24;    R13, R14, R15, R16, and R17 each independently            stand for a radical selected from the group consisting of —CF3, —C2F5, —CH2—CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, and n-hexyl;        or for a radical selected from the group consisting of phenyl, thiophenyl, furanyl, and pyridinyl, wherein the radical can in each case be optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, —CN, —NO2, —OH, —SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, —CF3, —O—CF3, —S—CF3, —SF5, —O—CH3, and —O—C2H5;            R23 stands for a hydrogen radical    and    R24 stands for a radical selected from the group consisting of methyl, —CH2—CN, ethyl, —CH2—CH2—CN, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, and n-hexyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Likewise, special preference is given to substituted cyclic urea derivatives of the above general formula I, in which    X stands for O, S or N—C≡N;    m is equal to 1;    n is equal to 1;    p1 and p2 each independently            stand for 0 or 1, the sum of p1 and p2 being 0 or 1;            R1, R2, R4, R8, R11, and R12 each stand for H;    R3 stands for F; Cl; Br, I; —OR16; —NR23S(═O)2R24;            or for a radical selected from the group consisting of —CF3, —C2F5, —CH2—CF3, isopropyl, sec-butyl, isobutyl, and tert-butyl;            R5 stands for H; F; Cl; Br or I;    R6 and R7 each stand for a hydrogen radical    or    R6 and R7, together with the interconnecting C—C bridge, form an unsubstituted phenylene radical;    R9 stands for H; F; Cl; Br; I or for a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl;    R10 stands for —NR23S(═O)2R24;    R16 stands for a radical selected from the group consisting of —CF3, —C2F5, and —CH2—CF3;    R23 stands for a hydrogen radical    and    R24 stands for a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, and n-hexyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Very special preference is given to substituted cyclic urea derivatives of the above general formula I, in which    X stands for O, S or N—C≡N;    m is equal to 1;    n is equal to 1;    p1 and p2 each independently            stand for 0 or 1, the sum of p1 and p2 being 0 or 1;            R1, R2, R4, R5, R8, R9, R11, and R12 in each case stand for H;    R3 stands for —OR16; —NR23S(═O)2R24;            or for a radical selected from the group consisting of —CF3, isopropyl, sec-butyl, isobutyl, and tert-butyl;            R6 and R7 each stand for a hydrogen radical    or    R6 and R7, together with the interconnecting C—C bridge, form an unsubstituted phenylene radical;    R10 stands for —NR23S(═O)2R24;    R16 stands for a radical selected from the group consisting of —CF3, —C2F5, and —CH2—CF3;    R23 stands for a hydrogen radical    and    R24 stands for a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neopentyl, and n-hexyl;in each case optionally in the form of one of the pure stereoisomers thereof, particularly enantiomers or diastereoisomers, or the racemates thereof or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
Even more preference is given to substituted cyclic urea derivatives of the above general formula I selected from the group consisting of    [1] N-[4-[3-(4-tert-butylbenzyl)-2-thioxo-imidazolidinylmethyl]phenyl]methanesulfonamide,    [2] N-[4-[3-(4-tert-butylbenzyl)-2-thioxo-2,3-dihydrobenzoimidazol-1-ylmethyl]phenyl]methanesulfonamide,    [3] N-[4-[3-(4-tert-butylbenzyl)-2-thioxotetrahydropyrimidin-1-ylmethyl]phenyl]methanesulfonamide,    [4] N-[4-[3-(4-tert-butylbenzyl)-2-oxo-imidazolidin-1-ylmethyl]phenyl]methanesulfonamide,    [5] N-[4-[3-(4-tert-butyl benzyl)-2-oxotetrahydropyrimidin-1-ylmethyl]phenyl]methanesulfonamide,    [6] N-[4-[3-(4-tert-butylbenzyl)-2-oxo-2,3-dihydrobenzoimidazol-1-ylmethyl]phenyl]methanesulfonamide,    [7] N-[4-[3-(4-trifluoromethoxybenzyl)-2-oxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl]methanesulfonamide,    [8] N-[4-[3-(4-trifluoromethoxybenzyl)-2-thioxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl]methanesulfonamide,    [9] N-[4-[3-(4-methanesulfonylaminobenzyl)-2-oxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl]methanesulfonamide, and    [10] N-{4-[2-oxo-3-(4-trifluoromethylbenzyl)-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide;in each case optionally in the form of corresponding salts, or in the form of corresponding solvates.
The invention further relates to a process for the preparation of compounds of the above general formula I, according to which at least one compound of the general formula II,
in which R6, R7, X, p1, and p2 have the meanings stated above, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and appropriate mixtures, optionally in the presence of at least one base, preferably in the presence of at least one metal hydride salt, more preferably in the presence of potassium and/or sodium hydride, or in the presence of at least one alkali metal carbonate salt, preferably in the presence of potassium and/or sodium carbonate, and at least one alkali metal iodide, preferably potassium and/or sodium iodide, is caused to react with at least one compound of the general formula III,
in which R1 to R5 and m have the meanings stated above and Y stands for a leaving group, preferably for a halogen radical, more preferably for a bromium atom or chlorine atom, to produce at least one compound of the general formula IV,
in which R1 to R7, X, p1, p2 and m have the meanings stated above, and this is optionally purified and/or isolated,or at least one compound of the general formula V,
in which R6, R7, p1, and p2 have the meanings stated above, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and appropriate mixtures, optionally in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of pyridine, triethylamine, and diisopropylethylamine, is caused to react with at least one compound of the general formula III to form at least one compound of the general formula VI,
in which R1 bis R7, m, p1, and p2 have the meanings stated above, and this is optionally purified and/or isolated, and at least one compound of the general formula VI is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and appropriate mixtures, optionally in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of pyridine, triethylamine, and diisopropylethylamine, with at least one compound of the general formula Z—C(═X)—Z in which X stands for an oxygen atom or sulfur atom and Z in each case for a leaving group, preferably in each case for a halogen radical, more preferably in each case for a chlorine atom, to form at least one compound of the general formula IV and this is optionally purified and/or isolated,orat least one compound of the general formula VII,
in which R6, R7, X, p1, and p2 have the meanings stated above, is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and appropriate mixtures, with at least one compound of the general formula VIII,
in which R1 to R5 and m have the meanings stated above, to produce at least one compound of the general formula IV, and this is optionally purified and/or isolated,and at least one compound of the general formula IV is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and corresponding mixtures, in the presence of at least one base, preferably in the presence of at least one metal hydride salt, more preferably in the presence of potassium and/or sodium hydride, or in the presence of at least one alkali metal carbonate salt, preferably in the presence of potassium and/or sodium carbonate, and at least one alkali metal iodide, preferably potassium and/or sodium iodide, with at least one compound of the general formula IX,
in which R8 to R12 and n have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —N(PG)2 group, wherein PG stands in each case for a protective group, preferably for a tert-butoxycarbonyl group or benzyloxycarbonyl group, or (PG)2 together with the interconnecting nitrogen atom form a cyclic protective group, preferably a phthalimide group, and Y stands for a leaving group, preferably for a halogen atom, more preferably for a chlorine or bromine atom, to produce at least one compound of the general formula XI,
in which R1 to R12, X, m, n, p1 and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —N(PG)2 group, in which PG has the meanings stated above, and this is optionally purified and/or isolated, and at least one compound of the general formula XI is converted, in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, acetone, diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and appropriate mixtures, in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of dimethylamine, triethylamine, diisopropylethylamine, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate, and cesium carbonate, more preferably in the presence of dimethylamine, or in the presence of at least one acid, preferably in the presence of at least one acid selected from the group consisting of hydrochloric acid, acetic acid, trifluoroacetic acid, citric acid, and sulfuric acid, or in the presence of hydrazine and/or phenylhydrazine or in the presence of at least one alkali metal boron hydride, preferably in the presence of sodium tetrahydridoborate, to form at least one compound of the general formula XII,
in which R1 bis R12, X, m, n, p1, and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NH2 group, and this is optionally purified and/or isolated,orat least one compound of the general formula IV is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and appropriate mixtures, in the presence of at least one base, preferably in the presence of at least one metal hydride salt, more preferably in the presence of potassium and/or sodium hydride, or in the presence of at least one alkali metal carbonate salt, preferably in the presence of potassium and/or sodium carbonate, and at least one alkali metal iodide, preferably potassium and/or sodium iodide, with at least one compound of the general formula XIII,
in which R8 to R12 and n have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NO2 group, and Y stands for a leaving group, preferably for a halogen radical, more preferably for a chlorine radical or bromine atom, to form at least one compound of the general formula XIV,
in which R1 bis R12, X, m, n, p1, and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NO2 group, and this is optionally purified and/or isolated, and at least one compound of the general formula XIV is converted, in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, acetone, diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and appropriate mixtures, in the presence of hydrogen and in the presence of a catalyst, preferably in the presence of a catalyst based on palladium and/or platinum, more preferably in the presence of palladium, to produce at least one compound of the general formula XII, in which R1 bis R12, X, m, n, p1, and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NH2 group, and this is optionally purified and/or isolated,and at least one compound of the general formula XII is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of acetone, diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and appropriate mixtures, optionally in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of pyridine, triethylamine, and diisopropylethylamine, with at least one compound of the general formula R24—S(═O)2—Z, in which R24 has the meanings stated above and Z stands for a leaving group, preferably for a halogen atom, more preferably for a chlorine atom, to form at least one compound of the general formula Ia,
in which R1 bis R12, X, m, n, p1, and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NH—S(═O)2—R24 group, in which R24 has the meanings stated above, and this is optionally purified and/or isolated,or at least one compound of the general formula IV is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and appropriate mixtures, in the presence of at least one base, preferably in the presence of at least one metal hydride salt, more preferably in the presence of potassium and/or sodium hydride, or in the presence of at least one alkali metal carbonate salt, preferably in the presence of potassium and/or sodium carbonate, and at least one alkali metal iodide, preferably potassium and/or sodium iodide, with at least one compound of the general formula XV,
in which R8 to R12 and n have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NH—S(═O)2—R24 group, in which R24 has the meanings stated above, to produce at least one compound of the general formula Ia, and this is optionally purified and/or isolated,and optionally at least one compound of the general formula Ia is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and appropriate mixtures, optionally in the presence of at least one base, preferably in the presence of at least one metal hydride salt, more preferably in the presence of potassium and/or sodium hydride, or in the presence of at least one alkali metal carbonate salt, preferably in the presence of potassium and/or sodium carbonate, and at least one alkali metal iodide, preferably potassium and/or sodium iodide, with at least one compound of the general formula R23—Z, in which R23 has the meanings stated above with the exception of hydrogen, and Z stands for a leaving group, preferably for a halogen atom, more preferably for a chlorine atom, to produce at least one compound of the general formula Ib,
in which R1 bis R12, X, m, n, p1, and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group, in which R23 and R24 have the meanings stated above, and this is optionally purified and/or isolated,and optionally at least one compound of the general formula Ib, in which R1 bis R12, m, n, p1, and p2 have the meanings stated above and X stands for an oxygen atom, provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group, in which R23 and R24 have the meanings stated above, is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of toluene, para-xylene, ortho-xylene, meta-xylene, dichloromethane, dimethylformamide, acetonitrile, and appropriate mixtures, with at least one compound of the general formula XVI
in which the phenyl radicals are each para-substituted by 1 or 2 substituents independently selected from the group consisting of methoxy, phenoxy, Cl, methyl, and Br, preferably by a phenoxy radical or methoxy radical, and more preferably by a methoxy radical, or with phosphorus pentasulfide, to produce at least one compound of the general formula Ib in which R1 to R12, m, n and p have the meanings stated above and X stands for or a sulfur atom, provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group, in which R23 and R24 have the meanings stated above, and this is optionally purified and/or isolated.
The invention further relates to a process for the preparation of compounds of the above general formula I, according to which at least one compound of the general formula II,
in which R6, R7, X, p1, and p2 have the meanings stated above, is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and corresponding mixtures, in the presence of at least one base, preferably in the presence of at least one metal hydride salt, more preferably in the presence of potassium and/or sodium hydride, or in the presence of at least one alkali metal carbonate salt, preferably in the presence of potassium and/or sodium carbonate, and at least one alkali metal iodide, preferably potassium and/or sodium iodide, with at least one compound of the general formula XVII,
in which R8 to R12 and n have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —N(PG)2 group, wherein PG in each case stands for a protective group, preferably for a tert-butoxycarbonyl group or benzyloxycarbonyl group, or two PG groups together with the interconnecting nitrogen atom form a cyclic protective group, preferably together with the interconnecting nitrogen atom a phthalimide group, or at least one of the substituents R8 to R12 stands for an —NO2 group, and Y stands for a leaving group, preferably for a halogen atom, more preferably for a chlorine radical or bromine atom, to produce at least one compound of the general formula XVIII,
in which R6 to R12, p1, p2 and n have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —N(PG)2 group or an —NO2 group, and this is optionally purified and/or isolated,orat least one compound of the general formula XIX,
in which R6, R7, X, p1, and p2 have the meanings stated above, is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane, and appropriate mixtures, with at least one compound of the general formula XX,
in which R8 to R12 and n have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —N(PG)2 group, in which PG in each case stands for a protective group, preferably for a tert-butoxycarbonyl group or benzyloxycarbonyl group, or (PG)2 together with the interconnecting nitrogen atom form a cyclic protective group, preferably a phthalimide group, or at least one of the substituents R8 to R12 stand for an —NO2 group, to produce at least one compound of the general formula XVIII and this is optionally purified and/or isolated,or at least one compound of the general formula V,
in which R6, R7, p1, and p2 have the meanings stated above, is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding mixtures, optionally in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of pyridine, triethylamine, and diisopropylethylamine, with at least one compound of the general formula XVII to produce at least one compound of the general formula XXI,
in which R6 to R12, p1, p2 and n have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —N(PG)2 group or an —NO2 group, and this is optionally purified and/or isolated, and at least one compound of the general formula XXI is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane, and appropriate mixtures, optionally in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of pyridine, triethylamine, and diisopropylethylamine, with at least one compound of the general formula Z—C(═X)—Z, in which X stands for an oxygen atom or sulfur atom and Z stands for a leaving group, preferably for a halogen radical, more preferably for a chlorine atom, to produce at least one compound of the general formula XVIII, and this is optionally purified and/or isolated,and at least one compound of the general formula XVIII is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and corresponding mixtures, in the presence of at least one base, preferably in the presence of at least one metal hydride salt, more preferably in the presence of potassium and/or sodium hydride, or in the presence of at least one alkali metal carbonate salt, preferably in the presence of potassium and/or sodium carbonate, and at least one alkali metal iodide, preferably potassium and/or sodium iodide, with at least one compound of the general formula III,
in which R1 to R5 and m have the meanings stated above and Y stands for a leaving group, preferably for a halogen radical, more preferably for a chlorine radical or bromine atom, to produce at least one compound of the general formula XXII,
in which R1 bis R12, X, m, n, p1, and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —N(PG)2 group or —NO2 group, and this is optionally purified and/or isolatedand at least one compound of the general formula XXII is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, acetone, diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene, and appropriate mixtures, in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of dimethylamine, triethylamine, diisopropylethylamine, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate, and cesium carbonate, more preferably in the presence of dimethylamine, or in the presence of at least one acid, preferably in the presence of at least one acid selected from the group consisting of hydrochloric acid, acetic acid, trifluoroacetic acid, citric acid, and sulfuric acid, or in the presence of hydrazine and/or phenylhydrazine or in the presence of at least one alkali metal boron hydride, preferably in the presence of sodium tetrahydridoborate, or in the presence of hydrogen and a catalyst, preferably a catalyst based on palladium and/or platinum, more preferably palladium, to produce at least one compound of the general formula XII,
in which R1 bis R12, X, m, n, p1, and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NH2 group, and this is optionally purified and/or isolated,and at least one compound of the general formula XII is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of acetone, diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene, and appropriate mixtures, optionally in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of pyridine, triethylamine, and diisopropylethylamine, with at least one compound of the general formula R24—S(═O)2—Z, in which R24 has the meanings stated above and Z stands for a leaving group, preferably for a halogen atom, more preferably for a chlorine atom, to produce at least one compound of the general formula Ia,
in which R1 bis R12, X, m, n, p1, and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NH—S(═O)2—R24 group, in which R24 has the meanings stated above, and this is optionally purified and/or isolated,and optionally at least one compound of the general formula Ia is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and corresponding mixtures, optionally in the presence of at least one base, preferably in the presence of at least one metal hydride salt, more preferably in the presence of potassium and/or sodium hydride, or in the presence of at least one alkali metal carbonate salt, preferably in the presence of potassium and/or sodium carbonate, and at least one alkali metal iodide, preferably potassium and/or sodium iodide, with at least one compound of the general formula R23—Z in which R23 has the meanings stated above with the exception of hydrogen and Z stands for a leaving group, preferably for a halogen atom, more preferably for a chlorine atom, to produce at least one compound of the general formula Ib,
in which R1 bis R12, X, m, n, p1, and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group, in which R23 and R24 have the meanings stated above, and this is optionally purified and/or isolated,and optionally at least one compound of the general formula Ib in which R1 bis R12 m, n, p1, and p2 have the meanings stated above and X stands for an oxygen atom, provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group, in which R23 and R24 have the meanings stated above, is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of toluene, para-xylene, meta-xylene, ortho-xylene, dichloromethane, dimethylformamide, acetonitrile, and appropriate mixtures, with at least one compound of the general formula XVI,
in which the phenyl radicals are each para-substituted by 1 or 2 substituents independently selected from the group consisting of methoxy, phenoxy, Cl, methyl, and Br, preferably by a phenoxy radical or methoxy radical, and more preferably by a methoxy radical, or with phosphorus pentasulfide, to produce at least one compound of the general formula Ib in which R1 to R12, m, n and p have the meanings stated above and X stands for a sulfur atom, provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group, in which R23 and R24 have the meanings stated above, and this is optionally purified and/or isolated.
The present invention further relates to a process for the preparation of compounds of the above general formula I, according to which at least one compound of the general formula II,
in which R6, R7, X, p1, and p2 have the meanings stated above, is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene, and appropriate mixtures, in the presence of at least one base, preferably in the presence of at least one metal hydride salt, more preferably in the presence of potassium and/or sodium hydride, or in the presence of at least one alkali metal carbonate salt, preferably in the presence of potassium and/or sodium carbonate, and at least one alkali metal iodide, preferably potassium and/or sodium iodide, with at least one compound of the general formula XXIII,
in which R8 bis R12, and n have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group and Y stands for a leaving group, preferably for a halogen atom, more preferably for a chlorine radical or bromine atom, to produce at least one compound of the general formula XXIV,
in which R6 to R12, p1, p2 and n the meanings stated above have provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group, and this optionally purified and/or isolated,and at least one compound of the general formula XXIV is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene, and appropriate mixtures, in the presence of at least one base, preferably in the presence of at least one metal hydride salt, more preferably in the presence of potassium and/or sodium hydride, or in the presence of at least one alkali metal carbonate salt, preferably in the presence of potassium and/or sodium carbonate, and at least one alkali metal iodide, preferably potassium and/or sodium iodide, with at least one compound of the general formula III,
in which R1 to R5 and m have the meanings stated above and Y stands for a leaving group, preferably for a halogen radical, more preferably for a chlorine or bromine atom, to produce at least one compound of the general formula Ib,
in which R1 bis R12, X, m, n, p1, and p2 have the meanings stated above, provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group, in which R23 and R24 have the meanings stated above, and this is optionally purified and/or isolated,and optionally at least one compound of the general formula Ib in which R1 bis R12 m, n, p1, and p2 have the meanings stated above and X stands for an oxygen atom, provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group, in which R23 and R24 have the meanings stated above, is caused to react, in a reaction medium, preferably in a reaction medium selected from the group consisting of toluene, para-xylene, ortho-xylene, meta-xylene, dichloromethane, dimethylformamide, acetonitrile, and appropriate mixtures thereof, with at least one compound of the general formula XVI,
in which the phenyl radicals are each para-substituted by 1 or 2 substituents independently selected from the group consisting of methoxy, phenoxy, Cl, methyl, and Br, preferably by a phenoxy radical or methoxy radical, and more preferably by a methoxy radical, or with phosphorus pentasulfide, to produce at least one compound of the general formula Ib in which R1 to R12, m, n, and p have the meanings stated above and X stands for a sulfur atom, provided that at least one of the substituents R8 to R12 stands for an —NR23—S(═O)2—R24 group, in which R23 and R24 have the meanings stated above, and this is optionally purified and/or isolated.
The compounds of the above formulas II, III, V, VII, IX, XIII, XV, XVI, XVII, XIX, XX and XXIII, and also of the general formulas R23—, R24—S(═O)2—Z and Z—C(═X)—Z are all commercially available and/or can be prepared by conventional methods known to the person skilled in the art.
The synthesis of compounds of the general formula II, in which X stands for N—C≡N, is also illustrated by the following scheme.

Compounds of the general formula XXX in which R stands for a C1-10 alkyl radical and preferably for methyl, ethyl, or tert-butyl, are caused to react with compounds of the general formula V, in which R6, R7, p1, and p2 have the meanings stated above, in a reaction medium, preferably in chloroform at a temperature of from 20° to 50° C. or in n-propanol at a temperature of from 20 to 100° C., to produce compounds of the general formula IIa, in which R6, R7, p1, and p2 have the meanings stated above.
The reactions described above can be carried out in each case under usual conditions well-known to the person skilled in the art, for example, as regards pressure and the order of addition of the components. Optionally, the optimal procedure under the respective conditions can be determined by the person skilled in the art using simple preliminary tests.
The intermediates and end products obtained by the aforementioned reactions can in each case be isolated and/or purified by conventional methods known to the person skilled in the art, if desired and/or necessary. Suitable clean-up techniques are, for example, extraction processes and chromatographic processes such as column chromatography or preparative chromatography.
All of the process steps described above and also the respective purification and/or isolation of intermediates or end-products can be carried out partially or completely under an inert gas atmosphere, preferably under a blanket of nitrogen or argon.
The substituted cyclic urea derivatives of the invention of the aforementioned general formulas I and the corresponding stereoisomers can be isolated either in the form of the free bases thereof or the free acids thereof or in the form of corresponding salts, particularly physiologically acceptable salts.
The free bases of the respective cyclic urea derivatives of the invention of the aforementioned general formulas I and also corresponding stereoisomers can be converted, for example, by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, or aspartic acid, to form the corresponding salts, preferably physiologically acceptable salts.
The free bases of the respective substituted cyclic urea derivatives of the aforementioned general formulas I and corresponding stereoisomers can likewise be caused to react with the free acid or a salt of a sugar substitute, such as saccharin, cyclamate or acesulfam, to form corresponding physiologically acceptable salts.
Similarly, the free acids of the substituted cyclic urea derivatives of the aforementioned general formulas I and corresponding stereoisomers can be converted to the corresponding physiologically acceptable salts by reaction with a suitable base. Mention may be made, for example, of the alkali-metal salts, alkaline earth metal salts, or ammonium salts [NHxR4-x]+ in which x is equal to 0, 1, 2, 3, or 4 and R stands for a linear or branched C1-4 alkyl radical.
The substituted cyclic urea derivatives of the invention of the aforementioned general formulas I and corresponding stereoisomers can, as well as the corresponding acids and the corresponding bases or salts of these compounds, optionally be obtained by conventional methods known to the person skilled in the art, also in the form of the solvates thereof, preferably in the form of the hydrates thereof.
If the substituted cyclic urea derivatives of the invention of the aforementioned general formulas I are obtained, following preparation thereof, in the form of a mixture of the stereoisomers thereof, preferably in the form of the racemates thereof or other mixtures of the various enantiomers and/or diastereoisomers thereof, these can be separated and optionally isolated by methods known to the person skilled in the art. Mention may be made, for example, of chromatographic separation methods, particularly liquid-chromatographic methods carried out under standard pressure or at elevated pressure, preferably MPLC and HPLC methods, and also methods of fractional crystallization. Particularly individual enantiomers can be separated from each other, eg, diastereoisomeric salts formed by means of HPLC on chiral stationary phase or by means of crystallization with chiral acids, say, (+)-tartaric acid, (−)-tartaric acid, or (+)-10-camphorsulfonic acid.
The substituted cyclic urea derivatives of the invention of the above general formula I and corresponding stereoisomers and also the corresponding acids, bases, salts, and solvates are toxicologically safe and are suitable therefore for use as pharmaceutical active substances in medicinal drugs.
The invention thus further relates to a medicinal drug containing at least one cyclic urea derivative of the invention of the above general formula I, in each case optionally in the form of any one of its pure stereoisomers, particularly enantiomers or diastereoisomers, its racemates or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically compatible adjuvants.
These medicinal drugs of the invention are particularly suitable for vanilloid receptor 1-(VR1/TRPV1) regulation, preferably vanilloid receptor 1-(VR1/TRPV1) inhibition and/or vanilloid receptor 1-(VR1/TRPV1) stimulation.
In another preferred embodiment, the medicinal drugs of the invention are suitable for prophylaxis and/or treatment of disorders or diseases that are at least partially mediated by vanilloid receptors 1.
Preferably, the medicinal drug of the invention is suitable for treatment and/or prophylaxis of one or more disorders selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain; arthralgia; migraine; depression; nervous disorders; neurotraumas; neurodegenerative disorders, preferably selected from the group consisting of multiple sclerosis, Morbus Alzheimer, Morbus Parkinson, and Morbus Huntington; cognitive dysfunctions, preferably cognitive deficiency states, more preferably memory defects; epilepsy; respiratory tract diseases, preferably selected from the group consisting of asthma and pneumonia; coughing; urinary incontinence; an overactive bladder (OAB); gastric ulcers; colitis syndrome; apoplectic strokes; eye irritations; cutaneous irritations; neurotic skin conditions; inflammatory diseases, preferably inflammation of the intestine; diarrhoea; pruritus; food intake disorders, preferably selected from the group consisting of bulimia, cachexia, anorexia, and obesity; medicine addiction; medicine abuse; withdrawal phenomena following medicine addiction; tolerance development to pharmaceutical preparations, preferably to natural or synthetic opioids; drug addiction; drug abuse; withdrawal phenomena following drug addiction; alcohol addiction; alcohol abuse and withdrawal phenomena following alcohol addiction; diuresis; antinatriuresis; affection of the cardiovascular system; for vigilance enhancement; for libido enhancement; for modulation of movement activity; for anxiolysis; for local anaesthesia and/or for inhibition of undesirable side effects, preferably selected from the group consisting of hyperthermia, hypertension, and bronchial constriction, caused by the administration of vanilloid receptor 1 (VR1/TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil.
The medicinal drug of the invention is more preferably suitable for treatment and/or prophylaxis of one or more disorders selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain; migraine; depression; neurodegenerative disorders, preferably selected from the group consisting of multiple sclerosis, Morbus Alzheimer, Morbus Parkinson, and Morbus Huntington; cognitive dysfunctions, preferably cognitive deficiency states, more preferably memory defects; urinary incontinence; overactive bladder (OAB); medicine addiction; medicine abuse; withdrawal phenomena following medicine addiction; tolerance development to pharmaceutical preparations, preferably tolerance development to natural or synthetic opioids; drug addiction; drug abuse; withdrawal phenomena following drug addiction; alcohol addiction; alcohol abuse and withdrawal phenomena following alcohol addiction.
The medicinal drug of the invention is most preferably suitable for treatment and/or prophylaxis of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain, and/or urinary incontinence.
The invention further relates to the use of at least one substituted cyclic urea derivative of the invention of the above general formula I, in each case optionally in the form of one of its pure stereoisomers, particularly enantiomers or diastereoisomers, its racemates or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically compatible adjuvants, for the preparation of a medicinal drug for vanilloid receptor 1-(VR1/TRPV1) regulation, preferably for vanilloid receptor 1-(VR1/TRPV1) inhibition and/or for vanilloid receptor 1-(VR1/TRPV1) stimulation.
Preference is given to the use of at least one substituted cyclic urea derivative of the above general formula I, in each case optionally in the form of one of its pure stereoisomers, particularly enantiomers or diastereoisomers, its racemates or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and also optionally one or more pharmaceutically compatible adjuvants for the preparation of a medicinal drug for the prophylaxis and/or treatment of disorders or diseases at least partially mediated by vanilloid receptors 1.
Particular preference is given to the use of at least one substituted cyclic urea derivative of the above general formula I, in each case optionally in the form of one of its pure stereoisomers, particularly enantiomers or diastereoisomers, its racemates or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and also optionally one or more pharmaceutically compatible adjuvants, for the preparation of a medicinal drug for treatment and/or prophylaxis of one or more disorders selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain; arthralgia; migraine; depression; nervous disorders; neurotraumas; neurodegenerative disorders, preferably selected from the group consisting of multiple sclerosis, Morbus Alzheimer, Morbus Parkinson, and Morbus Huntington; cognitive dysfunctions, preferably cognitive deficiency states, more preferably memory defects; epilepsy; respiratory tract diseases, preferably selected from the group consisting of asthma and pneumonia; coughing; urinary incontinence; overactive bladder (OAB); gastric ulcers; colitis syndrome; apoplectic strokes; eye irritations; cutaneous irritations; neurotic skin conditions; inflammatory diseases, preferably inflammation of the intestine; diarrhoea; pruritus; food intake disorders, preferably selected from the group consisting of bulimia, cachexia, anorexia, and obesity; medicine addiction; medicine abuse; withdrawal phenomena following medicine addiction; tolerance development to pharmaceutical preparations, preferably to natural or synthetic opioids; drug addiction; drug abuse; withdrawal phenomena following drug addiction; alcohol addiction; alcohol abuse and withdrawal phenomena following alcohol addiction; for diuresis; for antinatriuresis; for affection of the cardiovascular system; for vigilance enhancement; for libido enhancement; for modulation of movement activity; for anxiolysis; for local anaesthesia and/or for inhibition of undesirable side effects, preferably selected from the group consisting of hyperthermia, hypertension, and bronchial constriction, caused by administration of vanilloid receptor 1, (VR1/TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil, and capsavanil.
Very high preference is given to the use of at least one substituted cyclic urea derivative of the above general formula I, each optionally in the form of one of its pure stereoisomers, particularly enantiomers or diastereoisomers, its racemates or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or each in the form of a corresponding salt, or each in the form of a corresponding solvate, and also optionally one or more pharmaceutically compatible adjuvants, for the preparation of a medicinal drug for treatment and/or prophylaxis of one or more disorders selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain; migraine; depression; neurodegenerative disorders, preferably selected from the group consisting of multiple sclerosis, Morbus Alzheimer, Morbus Parkinson, and Morbus Huntington; cognitive dysfunctions, preferably cognitive deficiency states, more preferably memory defects; urinary incontinence; an overactive bladder (OAB); medicine addiction; medicine abuse; withdrawal phenomena following medicine addiction; tolerance development to pharmaceutical preparations, preferably tolerance development to natural or synthetic opioids; drug addiction; drug abuse; withdrawal phenomena following drug addiction; alcohol addiction; alcohol abuse and withdrawal phenomena following alcohol addiction.
Even more preference is given to the use of at least one substituted cyclic urea derivative of the above general formula I, each optionally in the form of one of its pure stereoisomers, particularly enantiomers or diastereoisomers, its racemates or in the form of a mixture of stereoisomers, particularly the enantiomers and/or diastereoisomers, in an arbitrary mixing ratio, or each in the form of a corresponding salt, or each in the form of a corresponding solvate, and also optionally one or more pharmaceutically compatible adjuvants for the preparation of a medicinal drug for treatment and/or prophylaxis of pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain, and/or urinary incontinence.
The medicinal drug of the invention is suitable for administration to adults and children including infants and babies.
The medicinal drug of the invention can exist as a liquid, semisolid, or solid pharmaceutical dosage form, for example, in the form of injection fluids, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, or aerosols, or in a multiparticular form, for example, in the form of pellets or granules, optionally compressed to tablets, filled into in capsules, or suspended in a liquid, and can be administered as such. In addition to at least one substituted cyclic urea derivative of the above general formula I, optionally in the form of one of its pure stereoisomers, particularly enantiomers or diastereoisomers, its racemates or in the form of mixtures of the stereoisomers, particularly the enantiomers or diastereoisomers, in an arbitrary mixing ratio, or optionally in the form of a corresponding salt or each in the form of a corresponding solvate, the medicinal drug of the invention usually contains further physiologically acceptable pharmaceutical adjuvants, preferably selected from the group consisting of support materials, fillers, solvents, diluents, surfactant, dyes, preservatives, blasting agents, slip agents, lubricants, flavors, and binding agents. The selection of the physiologically acceptable adjuvants and the amount thereof to be used depends on whether the medicinal drug is to be applied orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, eg, to infected parts of the skin, the mucous membrane, or the eyes. Preparations suitable for oral administration are preferably in the form of tablets, dragees, capsules, granules, pellets, drops, juices, and syrups, and preparations suitable for parenteral, topical, and inhalative administration are solutions, suspensions, readily reconstitutable dry preparations, and sprays.
The substituted cyclic urea derivatives of the invention of the above general formula I present in the medicinal drug of the invention can exist as suitable percutane administration forms in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration enhancing agents. Formulations suitable for oral or percutane application can be adapted for delayed release of the respective substituted cyclic urea derivatives of the invention of the above general formula I. The preparation of the medicinal drugs of the invention is carried out using conventional means, devices, methods and processes known in the prior art as described, for example, in “Remington's Pharmaceutical Sciences”, Editor A. R. Gennaro, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, particularly in Section 8, Chapter from 76 to 93. The corresponding description is incorporated herein by reference and is to be regarded as part of the disclosure.
The amount to be administered to the patients of the respective substituted cyclic urea derivatives of the invention of the above general formula I can vary and is, for example, dependent on the weight or age of the patient and also on the method of administration, the indication, and the severity of the disorder. Usually from 0.005 to 100 mg/kg, preferably from 0.05 to 75 mg/kg of body weight of the patient of at least one such compound of the invention are administered.
Pharmacological Methods:
I. Functional Investigation on the Vanilloid Receptor 1 (VRI/TRPV1 Receptor)
The agonistic or antagonistic action of the substances to be investigated on the vanilloid receptor 1 (VR1/TRPV1) of the species rat can be determined using the following assay. According to this assay, the Ca2+ influx through the receptor channel is quantified with the aid of a Ca2+-sensitive dye (Type Fluo-4, Molecular Probes Europe BV, Leiden Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
Method:
Complete medium: 50 mL of HAMS F12 Nutrient Mixture (Gibco Invitrogen GmbH, Karlsruhe, Germany) with
10% by volume of FCS (fetal calf serum, Gibco Invitrogen GmbH, Karlsruhe, Germany, heat-inactivated);
2 mM L-glutamine (Sigma, Munich, Germany);
1% by weight of AA solution (antibiotic/antimycotic solution, PAA, Pasching, Austria) and 25 ng/mL of Medium NGF (2.5 S, Gibco Invitrogen GmbH, Karlsruhe, Germany)
Cell culture plate: Poly-D-lysine-coated, black 96-hole plates with a clear bottom (96 well black/clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Karlsruhe, Germany) by diluting laminin to a concentration of 100 μg/mL with PBS (Ca—Mg-free PBS, Gibco Invitrogen GmbH, Karlsruhe, Germany). Aliquots having a concentration of 100 μg/mL of laminin are taken and stored at −20° C. The aliquots are diluted with PBS in the ratio 1:10 to 10 μg/mL of laminin and in each case 50 μL of the solution is pipeted into a hollow of the cell culture plate. The cell culture plates are incubated at 37° C. for at least two hours, the residual solution is aspirated and the hollows are in each case washed twice with PBS. The coated cell culture plates are stored with residual PBS and this is removed only directly before the addition of the cells.
Preparation of the Cells:
The vertebral column is removed from decapitated rats and this is laid directly in a cold, i.e. ice bath surrounded, HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) treated with 1% by volume (percent by volume) of an AA solution (antibiotic/antimycotic solution, PAA, Pasching, Austria). The vertebral column is cut in two longitudinally and the vertebral canal is removed together with fascias. Subsequently, the dorsal root ganglia (DRGs) is removed and in turn stored in cold HBSS buffer treated with 1% by volume of an AA solution. The DRGs completely freed from blood residues and spinal nerves are in each case transferred to 500 μL of cold collagenase Type 2 (PAA, Pasching, Austria) and incubated at 37° C. for 35 minutes. After addition of 2.5% by volume of trypsin (PAA, Pasching, Austria), the preparation is incubated at 37° C. for a further 10 minutes. On completion of incubation, the enzyme solution is carefully pipeted off and the DRGs are in each case treated with 500 μL of complete medium.
The DRGs are in each case repeatedly suspended, drawn through No. 1, No. 12 and No. 16 needles by means of a syringe and transferred to 50 mL Falcon tubes and these are filled to 15 mL with complete medium. The contents of each Falcon tube are in each case filtered through a 70 μm Falcon filter insert and centrifuged at 1200 revolutions and room temperature for 10 minutes. The resulting pellet is in each case taken up in 250 μL of complete medium and the cell count is determined.
The number of cells in the suspension is adjusted to 3 times 105 per mL and in each case 150 μL of this suspension is added to a hollow of the cell culture plates coated as described above. The plates are allowed to stand at 37° C., 5% by volume of CO2 and 95% relative humidity for two to three days in an incubator.
Subsequently, the cells are loaded with 2 μM Fluo-4 and 0.01% by volume of Pluronic F127 (Molecular Probes Europe BV, Leiden Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) at 37° C. for 30 min, washed 3× with HBSS buffer and, after a further incubation of 15 minutes at room temperature, employed in the FLIPR assay for Ca2+ measurement. The Ca2+-dependent fluorescence is measured before and after addition of substances (λex=488 nm, λem=540 nm). Quantification is carried out by the measurement of the highest fluorescence intensity (FC, fluorescence counts) over time.
FLIPR Assay:
The FLIPR protocol consists of 2 substance additions. Initially, the compounds to be tested (10 μM) are pipeted onto the cells and the Ca2+ influx is compared with the control (capsaicin 10 μM). Information is gained therefrom in % activation relative to the Ca2+ signal after addition of 10 μM capsaicin (CP). After incubation for 5 minutes, 100 nM of capsaicin are applied and the influx of Ca2+ is likewise determined.
Desensitizing agonists and antagonists lead to suppression of the Ca2+ influx. The % inhibition is calculated in comparison with the maximally achievable inhibition with 10 μM capsaicin.
Triplicate determinations (n=3) are carried out and these are repeated in at least 3 independent experiments (N=4).
Starting from the percentage of displacement by different concentrations of the compounds of the general formula I to be tested, IC50 inhibitory concentrations are calculated which bring about a 50 percent displacement of the capsaicin.
II. Formalin Test on Mice
The investigation for the determination of the antinociceptive action of the substituted cyclic urea derivatives of the invention is carried out in the formalin test on male mice (NMRI, 20 to 30 g body weight, Iffa, Credo, Belgium).
In the formalin-test, the first (early) phase (0 to 15 minutes after the formalin injection) and the second (late) phase (15 to 60 minutes after the formalin injection) are distinguished according to D. Dubuisson et al., Pain 1977, 4, 161-174. The early phase, as a direct reaction to the formalin injection, is a model of acute pain, whereas the late phase is regarded as a model of persistent (chronic) pain (T. J. Coderre et al., Pain 1993, 52, 259-285). The corresponding descriptions in the literature are included herein by reference and are considered to be part of the disclosure.
The substituted cyclic urea derivatives of the invention are investigated in the second phase of the formalin test in order to obtain information about substance actions on chronic/inflammatory pain.
The point in time of administration of the substituted cyclic urea derivatives before the formalin injection is chosen depending on the type of administration of the compounds of the invention. The intravenous administration of 10 mg/kg of body weight of the test substances is carried out 5 minutes before the formalin injection. This is carried out by means of a single subcutaneous formalin injection (20 μL, 1% strength aqueous solution) into the dorsal side of the right hind paw, such that with freemoving experimental animals a nociceptive reaction is induced which is manifested in marked licking and biting of the paw concerned.
Subsequently, the nociceptive behavior is continuously recorded by observation of the animals for an investigation period of three minutes in the second (late) phase of the formalin test (21 to 24 minutes after the formalin injection). The quantification of the pain behavior is carried out by summation of the seconds in which the animals show licking and biting of the relevant paw during the investigation period.
The comparison is in each case carried out using control animals, which instead of the compounds of the invention receive vehicle (0.9% strength aqueous sodium chloride solution) before formalin administration.
Based on the quantification of the pain behavior, the substance action in the formalin test is determined as the percentage change compared with the corresponding control.
After injection of substances which are antinociceptivally active in the formalin test, the described behavioral patterns of the animals, i.e. licking and biting, decreases or ceases.
For simplicity and illustrative purposes, the principles of the present invention are described by referring to various examples. One of ordinary skill in the art will readily recognize that the same principles are equally applicable to, and can be implemented in other forms, and that any such variation would be within those modifications that do not part from the true spirit and scope of the present invention. The invention is not limited in its application to the details of any particular formulation shown, since the invention is capable of other embodiments. The following examples are provided for illustrative purposes and do not and should not be understood to limit the claims appended hereto. The terminology used herein is for the purpose of description and not of limitation.